Omega-3 fatty acids are essential for normal human growth and development, and their therapeutic and preventative benefits with regard to cardiovascular disease and rheumatoid arthritis have been well documented (James et al., A. J. Clin. Nutr. 77: 1140-1145 (2003); Simopoulos, A. J. Clin, Nutr. 70: 560S-569S (1999)). Multiple studies have documented a protective role of fish oil and n-3 polyunsaturated fatty acids (PUFAs) with regard to the development of cardiovascular diseases. The cardioprotective benefits of fish oil have been largely attributed to 20 and 22 carbon fatty acids such as eicosapentaenoic acid (EPA, 20:5n-3) and docosahexanoic acid (DHA, 22:6, n-3) whose enrichment in cells and plasma lipoproteins results in decreased inflammation, thrombosis, blood pressure, arrhythmias, endothelial activation, and plasma triglyceride (TG) concentrations.
Mammals, including humans, can synthesize saturated fatty acids and monounsaturated (n-9) fatty acids but cannot synthesize either the (n-6) or the (n-3) double bond. The (n-3) and (n-6) fatty acids are essential components in cell membrane phospholipids and as a substrate for various enzymes; thus fatty acids containing these bonds are essential fatty acids and must be obtained in the diet. The (n-6) fatty acids are consumed primarily as linoleic acid [18:2(n-6)] from vegetable oils and arachidonic acid [AA, 20:4(n6)] from meats. The (n-3) fatty acids may be consumed as y-linolenic acid [GLA, 18:3(n-3)] from some vegetable oils. Longer-chain (n-3) fatty acids, mainly EPA and docosahexaenoic acid [DHA, 22:6(n-3)], are found in fish and fish oils (Hardman, J. Nutr. 134: 3427S-3430S (2004)).
In spite of the overwhelming evidence for the beneficial effects of fish oil, the consumption of n-3 PUFAs in the North American population is very low. Since the (n-3)- and (n-6) fatty acids cannot be interconverted in humans, the balance between (n-3) and (n-6) fatty acids in humans can only be achieved through appropriate diets. However, the current Western diet contains predominantly (n-6) fatty acids with a small portion of (n-3) fatty acids. In fact, it is estimated that actual dietary intakes of fatty acid from fish oil are as low as one-tenth of the levels recommended by the American Heart Association (Ursin, J. Nutr. 133: 4271-4272 (2003)). Such an imbalance in (n-3) and (n-6) fatty acids has been linked to various diseases, including asthma, cardiovascular diseases, arthritis, cancer.
Research has revealed that (n-3) and (n-6) fatty acids affect the various disease conditions through the action of two types of enzymes: cyclooxygenase (COX) and lipoxygenase (LOX). COX and LOX act on 20-carbon fatty acids to produce cell-signaling molecules. COX activity on AA or EPA produces prostaglandins or thromboxanes; LOX activity on AA or EPA produces the leukotrienes. The 2-series prostaglandins produced from AA tend to be proinflammatory and proliferative in most tissues. The 3-series prostaglandins produced from EPA tend to be less promotional for inflammation and proliferation. Thus, EPA-derived prostaglandins are less favorable for inflammation and for the development and the growth of cancer cells (Hardman, J. Nutr. 134: 3427S-3430S (2004)).
An alternative approach to affecting inflammatory diseases has been to supplement diets with the 18-carbon polyunsaturated fatty acid of the (n-6) series, y-linolenic acid [GLA, 18:3(n-6)]. This fatty acid is found primarily in the oils of the evening primrose and borage plants and to a lesser extent in meats and eggs. Animal data as well as some clinical studies suggest that dietary supplementation with GLA may attenuate the signs and symptoms of 20 chronic inflammatory diseases including rheumatoid arthritis and atopic dermatitis. Echium oil, another botanical oil, which contains stearidonic acid [SDA, 18:4 (n-3)], has been shown to have protective effects in hypertriglyceridemic patients.
However, a major concern in many dietary studies to date is that various sources of the PUFAs, whether it be fish oil, borage, evening primrose or echium oil or combinations of these oils, provide active ingredients (certain PUFAs) that are anti-inflammatory, but they also provide n-6 fatty acids that are potentially pro-inflammatory or that block the anti-inflammatory effects of the active PUFAs. Two such fatty acids are AA and linoleic acid [18:2 (n-6)]. The n-6 fatty acids are consumed primarily as linoleic acid from vegetable oils and AA from meats. Linoleic acid is converted to AA by a series of desaturation and elongation steps. The high amount of dietary linoleic acid is the primary culprit that has resulted in the major imbalance in omega 6 to omega 3 fatty acids observed in western nations. Diets high in linoleic acid have been demonstrated to be pro-inflammatory in several animal models.
Arachidonic acid is a twenty carbon n-6 fatty acid that is converted in mammals to products called leukotrienes, prostaglandins and thromboxanes. These products induce inflammation, and blocking their production utilizing drugs such as aspirin, ibuprofen, celecoxib (Celebrex™), and montelukast sodium (Singulair™) reduces signs and symptoms of inflammatory diseases including asthma and arthritis. In addition to the importance of AA in producing pro-inflammatory products, AA also regulates gene expression in mammals through transcription factors such as peroxisome proliferator-activated receptors (PPAR)-alpha leading to low level whole body inflammation. As indicated above, recent studies reveal that AA is present in high concentrations in many items in our food supply. Ironically, it is found in high concentrations in certain fish. AA in human diets has been correlated with increased levels of pro-inflammatory products, platelet aggregation and atherosclerosis.